The present invention relates to an improved process for preparing statine ((3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), the phenyl analog of statine ((3X,4X)-4-amino-3-hydroxy-5-phenylpentanoic acid), the cyclohexyl analog of statine ((3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid) and derivatives thereof as well as other valuable intermediates used in the process.
Statine, the phenyl and cyclohexyl analogs of statine and derivatives thereof are of pharmaceutical interest as key intermediates in the preparation of inhibitors of the enzyme renin.
Renin is a natural enzyme which is released into the blood stream from the kidney. It cleaves its natural substrate, angiotensinogen, releasing a decapeptide, angiotensin I. This in turn is cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renin have been sought as agents for control of hypertension, hyperaldosteronism and congestive heart failure.
A number of syntheses of statine and its analogs have been reported. The majority of these are based on the aldol condensation of an N-protected-L-amino aldehyde with a metallated acetic acid derivative. The aforementioned syntheses suffer the drawbacks of difficult in preparation via organometallics and carbanion chemistry and subsequent ease of racemization of the amino aldehyde, a need for separation of disastereoisomers and in some cases a need for expensive and exotic reagents.
European Patent Application 210896-A and a publication by Jouin, P. and Castro, B., Journal of the Chemical Society Perkin I, pages 1177-1182 (1987) disclose a process for preparing a compound of formula A ##STR1## wherein W=hydrogen or a protecting group;
R.sub.1 =1-6 carbon alkyl, methoxyalkyl, benzyloxyalkyl, methylthioalkyl, phenylthioalkyl, benzylthioalkyl, optionally protected aminoalkyl, mono- or dialkylaminoalkyl, hydroxyalkyl, optionally esterified carboxyalkyl, optionally alkylated carbamoylalakyl, lower alkyl substituted on the same carbon atom by NH.sub.2 and optionally esterified COOH, 2-6 carbon alkenyl, methoxyalkenyl, phenoxyalkenyl, benzyloxyalkenyl, methylthioalkenyl, phenylthioalkenyl, benzylthioalkenyl, optionally protected aminoalkenyl, mono- or dialkylaminoalkenyl, optionally esterified carboxyalkenyl, optionally alkylated carbamoylalkenyl, 2-6 carbon alkynyl, Cy-A-, Cy-O-A'- or R.sub.3 S-A-; PA1 Cy=aromatic or alicyclic hydrocarbon, or heterocycle containing an O or S atom or 1 or 2 N atoms, all optionally substituted by 1-3 of OH, lower alkyl, lower alkoxy, CF.sub.3, NO.sub.2 or halogen; PA1 A=a direct bond, 1-5 carbon alkylene or 2-5 carbon alkenylene; PA1 (a) reacting a compound of formula V ##STR13## wherein R is as defined above with a hydroxyl protecting reagent at about 0.degree. C. to about 50.degree. C. to afford a compound of formula IV ##STR14## wherein R.sub.2 is (CH.sub.3).sub.3 Si, or ##STR15## and R is as defined above;
A'=1-5 carbon alkylene or 2-5 carbon alkenylene;
R.sub.3 =an S-protecting group;
R.sub.2 =hydrogen, alkali(ne earth) metal, lower alkyl, or benzyl optionally substituted by lower alkyl, halogen or NO.sub.2, by reacting a compound of formula ##STR2## wherein W.sup.1 =an N- protecting group and R.sub.1 is as defined above, in an acidic or basic medium to afford a compound of formula A.
Further, Andrew, R. G., et al, Tetrahedron Letters, Vol. 28, pages 6535-6538 (1987) describe the preparation of several (3S,4S) and (3S,4R) statine derivatives by attack of nucleophiles on N-BOC-lactams ##STR3##
However, the aforementioned processes, unlike the process of the present invention, require the use of expensive reagents and exacting reaction conditions. Both of these requirements are undesirable for the large scale syntheses of compounds of the present invention.
The process of the present invention proceeds in high yield and is amenable to large scale synthesis.